Just as repressors function through co-repressors that bind to their repression domains, the activation domains of DNA-binding activators function by binding multisubunit co-activator complexes, protein complexes that interact with or modify chromatin, Pol II, or general transcription factors to activate transcription. One of the first co-activator complexes to be characterized was the yeast SAGA complex. Early genetic studies indicated that full activity of the Gcn4 activator required a protein called Gcn5. The clue to Gcn5’s function came from biochemical studies of a histone acetylase purified from the protozoan Tetra hymena, the first histone acetylase to be purified. Sequence analysis revealed homology between the Tetrahymena protein and yeast Gcn5, which was soon shown to have histone acetylase activity as well. Further genetic and biochemical studies revealed that Gcn5 is one subunit of a multiprotein co-activator complex, named the SAGA complex after genes encoding some of the subunits. Another subunit of this his tone acetylase complex binds to activation domains in multiple yeast activator proteins, including Gcn4. The model shown in Figure 1b is consistent with the observation that nucleosomes near the promoter region of a gene regulated by the Gcn4 activator are specifically hyperacetylated compared with most histones in the cell. This activator directed hyperacetylation of nucleosomes near a promoter region opens the chromatin structure so as to facilitate the binding of other proteins required for transcription initiation. The chromatin structure is less condensed than most chromatin, as indicated by its sensitivity to digestion with nucleases in isolated nuclei.

Fig1. Proposed mechanism of histone deacetylation and hyperacetylation in yeast transcriptional control. (a) Repressor directed deacetylation of histone N-terminal tails. The DNA-binding domain (DBD) of the repressor Ume6 interacts with a specific upstream control element of the genes it regulates, called URS1. The Ume6 repression domain (RD) binds Sin3, a subunit of a multiprotein complex that includes Rpd3, a histone deacetylase. Deacetylation of histone N-terminal tails on nucleosomes in the region of the Ume6-binding site inhibits binding of general transcription factors at the TATA box, thereby repressing gene expression. (b) Activator directed hyperacetylation of histone N-terminal tails. The DNA-binding domain of the activator Gcn4 interacts with specific upstream activating sequences (UAS) of the genes it regulates. The Gcn4 activation domain (AD) then interacts with a multiprotein histone acetylase complex that includes the Gcn5 catalytic subunit. Subsequent hyperacetylation of histone N-terminal tails on nucleosomes in the vicinity of the Gcn4-binding site facilitates access by the general transcription factors required for initiation. Repression and activation of many genes in higher eukaryotes occur by similar mechanisms.

In addition to leading to the decondensation of chromatin, the acetylation of specific histone lysines generates binding sites for proteins containing bromodomains. A bro modomain is a sequence of about 110 amino acids that folds into a domain that binds acetylated lysine. One or more bromodomains are found in several chromosome-associated proteins that contribute to transcriptional activation. For example, a subunit of the general transcription factor TFIID contains two bromodomains, which bind to acetylated nucleosomes with high affinity. Recall that TFIID binding to a promoter initiates assembly of an RNA polymerase II preinitiation complex (see Figure2). Nucleosomes at promoter regions of virtually all active genes have acetylated lysines in their H3 and H4 histone tails.

Fig2. Model for the sequential assembly of an RNA polymerase II preinitiation complex. The indicated general transcription factors and purified RNA polymerase II (Pol II) bind sequentially to TATA box DNA to form a preinitiation complex (PIC). ATP hydrolysis then provides the energy for the unwinding of DNA at the transcription start site by a TFIIH helicase subunit that pushes downstream DNA into the polymerase. The DNA is held in position in the PIC by binding of the TATA box by the TBP subunit of TFIID, and the resulting strain on the structure of the duplex DNA assists the N-terminal region of TFIIB and Pol II to melt the DNA at the transcription start site, forming the transcription bubble. As Pol II initiates transcription in the resulting open complex, the polymerase transcribes away from the promoter, its CTD becomes phosphorylated by the TFIIH kinase domain, and the general transcription factors dissociate from the promoter. See S. Sainsbury, C. Berrnecky, and P. Cramer, 2015, Nat. Rev. Mol. Cell Biol. 16:129.

A similar activation mechanism operates in higher eukaryotes. Mammalian cells contain multisubunit histone acetylase co-activator complexes that are homologous to the yeast SAGA complex. They also express two related 300-kDa, multidomain proteins called CBP and p300, which function similarly. As noted earlier, one domain of CBP binds the phosphorylated acidic activation domain in the CREB transcription factor. Other domains of CBP inter act with different activation domains in other activators. Yet another domain of CBP has histone acetylase activity, and another CBP domain associates with additional multisubunit histone acetylase complexes. CREB and many other mammalian activators function in part by directing CBP and the associated histone acetylase complex to specific nucleosomes, where they acetylate histone tails, facilitating the interaction of general transcription factors with promoter DNA.

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مواضيع ذات صلة

Epigenetic Regulation of Transcription

Chromatin-Remodeling Complexes Help Activate or Repress Transcription

Repressors Can Direct Histone Deacetylation at Specific Genes

Formation of Heterochromatin Silences Gene Expression at Telomeres, near Centromeres, and in Other Regions

Multiprotein Complexes Form on Enhancers

Transcription Factor Interactions Increase Gene-Control Options

Structurally Diverse Activation and Repression Domains Regulate Transcription

Electrophoresis of Nucleic Acids

Regulation of Transcription Factor Activity

Activators Are Composed of Distinct Functional Domains

DNase I Footprinting and EMSA Detect Protein-DNA Interactions

Most Eukaryotic Genes Are Regulated by Multiple Transcription-Control Elements